16-70252728-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001605.3(AARS1):c.2900A>T(p.Lys967Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,614,088 control chromosomes in the GnomAD database, including 157 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K967N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0094 (10 hom., cov: 33)
  • Exomes 𝑓: 0.012 (147 hom.)
• Consequence: AARS1 NM_001605.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.57

Genes affected

AARS1 (HGNC:20): (alanyl-tRNA synthetase 1) The human alanyl-tRNA synthetase (AARS) belongs to a family of tRNA synthases, of the class II enzymes. Class II tRNA synthases evolved early in evolution and are highly conserved. This is reflected by the fact that 498 of the 968-residue polypeptide human AARS shares 41% identity witht the E.coli protein. tRNA synthases are the enzymes that interpret the RNA code and attach specific aminoacids to the tRNAs that contain the cognate trinucleotide anticodons. They consist of a catalytic domain which interacts with the amino acid acceptor-T psi C helix of the tRNA, and a second domain which interacts with the rest of the tRNA structure. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0089383125).
• BP6: Variant 16-70252728-T-A is Benign according to our data. Variant chr16-70252728-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 220723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-70252728-T-A is described in Lovd as [Benign]. Variant chr16-70252728-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00941 (1433/152320) while in subpopulation NFE AF= 0.0139 (945/68032). AF 95% confidence interval is 0.0132. There are 10 homozygotes in gnomad4. There are 700 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AARS1	NM_001605.3	c.2900A>T	p.Lys967Met	missense_variant	21/21	ENST00000261772.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AARS1	ENST00000261772.13	c.2900A>T	p.Lys967Met	missense_variant	21/21	1	NM_001605.3	P1

Frequencies

GnomAD3 genomes AF: 0.00942 AC: 1433 AN: 152202 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00762

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00992 AC: 2493 AN: 251344 Hom.: 27 AF XY: 0.00994 AC XY: 1351 AN XY: 135866

Gnomad AFR exome AF: 0.00302

Gnomad AMR exome AF: 0.00798

Gnomad ASJ exome AF: 0.0255

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00173

Gnomad FIN exome AF: 0.00853

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0123 AC: 17971 AN: 1461768 Hom.: 147 Cov.: 31 AF XY: 0.0120 AC XY: 8758 AN XY: 727200

Gnomad4 AFR exome AF: 0.00230

Gnomad4 AMR exome AF: 0.00847

Gnomad4 ASJ exome AF: 0.0290

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.00806

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.00941 AC: 1433 AN: 152320 Hom.: 10 Cov.: 33 AF XY: 0.00940 AC XY: 700 AN XY: 74474

Gnomad4 AFR AF: 0.00241

Gnomad4 AMR AF: 0.0110

Gnomad4 ASJ AF: 0.0280

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00762

Gnomad4 NFE AF: 0.0139

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0144 Hom.: 8

Bravo AF: 0.00949

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0140 AC: 54

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0135 AC: 116

ExAC AF: 0.00959 AC: 1164

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.0150

EpiControl AF: 0.0142

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	AARS1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Charcot-Marie-Tooth disease axonal type 2N Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Charcot-Marie-Tooth disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Charcot-Marie-Tooth disease axonal type 2N;C4225361:Developmental and epileptic encephalopathy, 29;C5562044:Leukoencephalopathy, hereditary diffuse, with spheroids 2;C5562057:Trichothiodystrophy 8, nonphotosensitive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.39
MVP		0.68
MPC		0.78
ClinPred		0.028	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.13
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35744709; hg19: chr16-70286631; COSMIC: COSV99028685; COSMIC: COSV99028685;